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L Demeter

Publications and source records attributed to L Demeter.

11 recordsLinked to original sources
PubMed2001

A Phase 1 study of a recombinant viruslike particle vaccine against human papillomavirus type 11 in healthy adult volunteers.

Viruslike particles (VLPs) produced from the L1 protein of several papillomaviruses have induced protection from infection after live challenge in animal models. In the present study, the safety and immunogenicity of a human papillomavirus (HPV)--11 L1 VLP candidate vaccine were measured in a phase 1, dose-finding trial in humans. The vaccine was well tolerated and induced high levels of both binding and neutralizing antibodies. Marked increases in lymphoproliferation to HPV--11 L1 antigens were noted after the second vaccination. In addition, lymphoproliferation was induced after vaccination in peripheral blood mononuclear cells (PBMC) stimulated with heterologous L1 VLP antigens of HPV types 6 and 16. Statistically significant increases in HPV antigen--specific interferon--gamma and interleukin-5 production were measured from PBMC culture supernatants. This candidate HPV VLP vaccine induced robust B and T cell responses, and T cell helper epitopes appear to be conserved across HPV types.

Adolescent↗
PubMed2001

International perspectives on antiretroviral resistance. Phenotypic and genotypic resistance assays: methodology, reliability, and interpretations.

Phenotypic and genotypic resistance assays-methods to measure the susceptibility of HIV to drug therapy-are becoming widely available to clinicians for use in aiding long-term antiretroviral treatment planning. Phenotypic tests assess the actual response of a patient's viral isolate to individual antiretroviral drugs in culture, and genotypic tests sequence viral DNA, providing an inferred measure of resistance based on the evaluator's knowledge of established HIV-1 genetic mutational patterns for resistance to antiretroviral drugs. These tests, when used as intended, can provide information useful in planning successful antiretroviral regimens. Both types of assays have been shown to provide reliable and reproducible measures of resistance, with certain caveats: accuracy depends on the experience of the interpreter and laboratory; results from the available tests are not interchangeable, and clinically relevant thresholds of resistance have not been fully defined. Because of pharmacokinetic and cross-resistance issues, the extrapolation of single-drug data to combination regimens is difficult to accomplish and must be pooled with treatment and viral load history to best identify effective subsequent treatment regimens. This article describes the experience to date establishing the efficacy, accuracy, reproducibility, and limitations of the phenotypic and genotypic resistance assays used today.

Anti-HIV Agents↗
PubMed2001

International perspectives on antiretroviral resistance. Clinical utility of resistance testing: retrospective and prospective data supporting use and current recommendations.

Data from retrospective and prospective studies support use of genotypic and phenotypic resistance assays to guide treatment changes when initial or subsequent antiretroviral regimens fail. Several retrospective studies have shown that response to antiretroviral therapy can be predicted based on genotypic analysis of HIV, with baseline genotypic evidence of resistance predicting virologic failure. Other retrospective analyses demonstrated that phenotypic drug sensitivity correlates with increased viral load suppression, particularly when virus remains sensitive to two or three drugs at initiation of the regimen. Furthermore, prospective studies such as VIRADAPT and Genotype-Assisted Antiretroviral Resistance Testing (GART) have substantiated that drug selection based on genotypic assay results yield superior viral suppression compared with empiric treatment assignment. One additional study suggested significant improvement in short-term virologic outcome when phenotypic testing was used to guide treatment selection. Based on these findings, resistance testing is currently recommended for patients with acute HIV infection, those who have failed one or more antiretroviral regimens, and pregnant women. Although these tests move toward becoming a standard of care, several research questions remain: the long-term benefit of resistance testing is not yet certain, the interpretation of specific genotypic resistance patterns needs to be better defined, and clinical cut-off points for phenotypic resistance need to be established. As these issues continue to be studied, resistance testing likely will prove a reliable tool to help plan successful ART strategies.

Anti-HIV Agents↗
PubMed2000

Autonomic performance and dehydroepiandrosterone sulfate levels in HIV-1-infected individuals: relationship to TH1 and TH2 cytokine profile.

BACKGROUND: Products of immune activation, including cytokines and lipid membrane derivatives, have been implicated in the pathogenesis of the neurologic sequelae, including autonomic dysfunction, associated with human immunodeficiency virus 1 (HIV-1) infection. In animal models, autonomic and endocrine dysfunction are associated with an altered cytokine profile. OBJECTIVES: To investigate the relationship between markers of immune activation (beta(2)-microglobulin), HIV-1 disease progression (CD4(+) cell count and viral load), and autonomic nervous system performance and to assess the relationship between autonomic performance, plasma levels of dehydroepiandrosterone sulfate (DHEAS), and T(H)1 and T(H)2 cytokine profile. METHODS: Thirty-one HIV-1-infected individuals and 22 HIV-1-negative controls were evaluated with a comprehensive neurologic, neuropsychological, and autonomic examination. Interleukin 4 and interferon gamma were measured by enzyme-linked immunosorbent assay in the supernatant of stimulated peripheral blood mononuclear cells. RESULTS: A composite measure of autonomic performance (AZ score) was significantly lower (worse autonomic function) in patients compared with controls (P=.04). A lower AZ score was associated with higher beta(2)-microglobulin serum levels and a lower CD4(+) cell count. Interleukin 4 levels were significantly inversely associated with AZ score (P=.01), whereas interferon gamma levels were significantly positively associated with DHEAS levels (P=.04). CONCLUSIONS: Our data show significant associations between markers of immune activation and disease progression and a composite measure of autonomic function in HIV-1-infected individuals. In addition, they suggest that poor autonomic function and low DHEAS plasma levels tend to be associated with an unbalanced cytokine profile.

Adult↗
PubMed1999

Efficacy and safety of delavirdine mesylate with zidovudine and didanosine compared with two-drug combinations of these agents in persons with HIV disease with CD4 counts of 100 to 500 cells/mm3 (ACTG 261). ACTG 261 Team.

To evaluate the antiretroviral activity of delavirdine mesylate, a non-nucleoside reverse transcriptase inhibitor of HIV-1, we performed a phase II, randomized, double-blind, multicenter trial comparing the three-drug combination of delavirdine with zidovudine and didanosine to two-drug combinations of these drugs. Patients with CD4 cell counts between 100 and 500 cells/mm3 without prior or <6 months of monotherapy with zidovudine or didanosine were randomized to one of four arms and observed on a follow-up basis for 48 weeks. In total, 544 patients were evaluated. In those assigned to the three-drug regimen, mean short-term (weeks 4-12) and long-term (weeks 40-48) change in CD4 cells from baseline were 49.3+/-8.1 and 65.4+/-13.4 cells/mm3, respectively; mean short-term and long-term HIV-1 RNA changes from baseline were -1.13 log10+/-0.12 and -0.73+/-0.12 copies/ml, respectively. These responses in CD4 cell counts and HIV-1 RNA levels were better in comparisons with each of the two-drug arms at all study points; however, differences were not consistently significant. Gastrointestinal side effects were experienced by 33% of patients (178 of 544), and 30% (121 of 407) receiving delavirdine experienced rash, only one case of which was severe. In this study, therapy with delavirdine + zidovudine + didanosine was safe and showed modest, but not always significant, antiviral activity and CD4 cell count benefit compared with two-drug regimens with these agents. Key

Adult↗
PubMed1999

Worldwide evaluation of DNA sequencing approaches for identification of drug resistance mutations in the human immunodeficiency virus type 1 reverse transcriptase.

A panel (ENVA-1) of well-defined blinded samples containing wild-type and mutant human immunodeficiency virus type 1 (HIV-1) reverse transcriptase was analyzed by automated DNA sequencing in 23 laboratories worldwide. Drug resistance mutations at codons 41, 215, and 184 were present in the panel samples at different ratios to the wild type. The presence of mutant genotypes was determined qualitatively and quantitatively. All laboratories reported the presence of sequence heterogeneities at codons 41, 215, and 184 in one or more of the panel samples, though not all reported the correct codon genotypes. Two laboratories reported a mutant genotype in samples containing only the wild type, whereas two and three laboratories failed to detect the mutant genotypes at codons 41 and 215, respectively, in a completely mutant DNA population. Mutations present at relative concentrations of 25% of the total DNA population were successfully identified by 13 of 23, 10 of 23, and 16 of 23 labs for codons 41, 215, and 184Val, respectively. For more than 80% of those laboratories that qualitatively detected the presence of a mutation correctly, the estimated wild type/mutant ratio was less than 25% different from the input ratio in those samples containing 25 to 50% or 75% mutant input. This first multicenter study on the quality of DNA sequencing approaches for identifying HIV-1 drug resistance mutations revealed large interlaboratory differences in the quality of the results. The application of these procedures in their current state would in several cases lead to inaccurate or even incorrect diagnostic results. Therefore, proper quality control and standardization are urgently needed.

Codon↗
PubMed1997

Longitudinal analysis of quantitative virologic measures in human immunodeficiency virus-infected subjects with > or = 400 CD4 lymphocytes: implications for applying measurements to individual patients. National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group.

The natural variability of quantitative virologic measures among human immunodeficiency virus (HIV) type 1-infected persons was prospectively studied in 29 untreated persons with >600 CD4 cells/microL and in 15 persons receiving zidovudine monotherapy who had 400-550 CD4 cells/microL at study entry. Cell- and plasma-associated infectious HIV-1, provirus, and virion RNA were determined monthly as were numbers of CD4 and CD8 cells. HIV-1 replication varied widely among subjects with similar CD4 cell counts. The within-individual variability was significantly less than the variability between subjects for all virologic measures. Plasma virion HIV-1 RNA levels had the least variability. A mathematical model was devised to assess whether a potential therapeutic intervention significantly alters peripheral HIV-1 load. The model indicated that three measurements of plasma RNA would be outside the 95th percentile for the expected change in an individual due to natural variability. This approach can be used to accurately assess a therapeutic intervention among persons with low plasma HIV-1 titers.

Adult↗
PubMed1996

Prognostic value of plasma human immunodeficiency virus type 1 (HIV-1) RNA levels in patients with advanced HIV-1 disease and with little or no prior zidovudine therapy. AIDS Clinical Trials Group Protocol 116A/116B/117 Team.

The association of plasma human immunodeficiency virus type 1 (HIV-1) RNA level at study entry and over time with clinical progression was evaluated in 187 patients from AIDS Clinical Trials Group protocol 116A who had little or no prior zidovudine treatment. Three-fold-higher HIV-1 RNA levels at study entry and 3-fold increases by week 8 were associated with progression (relative hazard [RH], 1.67; 95% confidence limits [CL], 1.20, 2.32; and RH, 1.45; CL, 1.02, 2.05, respectively). Having 3-fold-higher CD4 cell count at entry was independently associated with a 52% reduction in risk for progression (adjusted RH, 0.48; CL, 0.33, 0.70). When stratified by length of prior zidovudine therapy, RNA level was predictive in drug-naive patients (adjusted RH, 1.87; CL, 1.23, 2.85) but not predictive in patients with up to 16 weeks of prior therapy (adjusted RH, 1.11; CL, 0.70, 1.76). Analysis suggests that the acquisition of mutations at HIV-1 reverse transcriptase codons 215 and 74 is associated with subsequent increases in HIV-1 RNA level (relative risk, 7.00; CL, 0.86, 56.90).

Acquired Immunodeficiency Syndrome↗
PubMed1987

Group selection of early replicators and the origin of life.

A major problem of the origin of life has been that of information integration. As Eigen (1971) has shown, a mutant distribution of RNAs replicating without the aid of a replicase cannot integrate sufficient information for the functioning of a higher-level unit utilizing several types of encoded enzymes. He proposed the hypercycle model to bridge this gap in prebiology. It can be shown by a nonlinear game model, incorporating mutation of a hypercycle, that the selection properties of hypercycles make them inefficient information integrators as they cannot compete favourably with all kinds of less efficient information carriers or mutationally coupled hypercycles. The stochastic corrector model is presented as an alternative resolution of Eigen's paradox. It assumes that replicative templates are competing within replicative compartments, whose selective values depend on the internal template composition via a catalytic acid in replication and "metabolism". The dynamics of template replication are analyzed by numerical simulation of master equations. Due to the stochasticity in replication and compartment fission the best compartment types recur. An Eigen equation at the compartment level is set up and calculated. Even selfish template mutants cannot destroy the system though they make it less efficient. The genetic information of templates is evaluated at both levels, and the higher (compartment) level successfully constrains the lower (template) one. Compartmentation together with stochastic effects is sufficient to integrate information dispersed in competitive replicators. Compartment selection is considered to be group selection of replicators. Implications for the origin of life are discussed.

Biological Evolution↗
PubMedDate not supplied

Safety systems.

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Legislation as Topic↗